Atrial fibrillation in embolic stroke of undetermined source: role of advanced imaging of left atrial function

\ua9 The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. AIMS: Atrial fibrillation (AF) is detected in over 30% of patients following an embolic stroke of undetermined source (ESUS) when monitored with an implantable loop recorder (ILR). Identifying AF in ESUS survivors has significant therapeutic implications, and AF risk is essential to guide screening with long-term monitoring. The present study aimed to establish the role of left atrial (LA) function in subsequent AF identification and develop a risk model for AF in ESUS. METHODS AND RESULTS: We conducted a single-centre retrospective case-control study including all patients with ESUS referred to our institution for ILR implantation from December 2009 to September 2019. We recorded clinical variables at baseline and analysed transthoracic echocardiograms in sinus rhythm. Univariate and multivariable analyses were performed to inform variables associated with AF. Lasso regression analysis was used to develop a risk prediction model for AF. The risk model was internally validated using bootstrapping. Three hundred and twenty-three patients with ESUS underwent ILR implantation. In the ESUS population, 293 had a stroke, whereas 30 had suffered a transient ischaemic attack as adjudicated by a senior stroke physician. Atrial fibrillation of any duration was detected in 47.1%. The mean follow-up was 710 days. Following lasso regression with backwards elimination, we combined increasing lateral PA (the time interval from the beginning of the P wave on the surface electrocardiogram to the beginning of the A\u27 wave on pulsed wave tissue Doppler of the lateral mitral annulus) [odds ratio (OR) 1.011], increasing Age (OR 1.035), higher Diastolic blood pressure (OR 1.027), and abnormal LA reservoir Strain (OR 0.973) into a new PADS score. The probability of identifying AF can be estimated using the formula. Model discrimination was good [area under the curve (AUC) 0.72]. The PADS score was internally validated using bootstrapping with 1000 samples of 150 patients showing consistent results with an AUC of 0.73. CONCLUSION: The novel PADS score can identify the risk of AF on prolonged monitoring with ILR following ESUS and should be considered a dedicated risk stratification tool for decision-making regarding the screening strategy for AF in stroke.One-third of patients with a type of stroke called embolic stroke of undetermined source (ESUS) also have a heart condition called atrial fibrillation (AF), which increases their risk of having another stroke. However, we do not know why some patients with ESUS develop AF. To figure this out, we studied 323 patients with ESUS and used a special device to monitor their heart rhythm continuously for up to 3 years, an implantable loop recorder. We also looked at their medical history, performed a heart ultrasound, and identified some factors that increase the risk of identifying AF in the future. Factors associated with future AF include older age, higher diastolic blood pressure, and problems with the co-ordination and function of the upper left chamber of the heart called the left atrium.Based on these factors, we created a new scoring system that can identify patients who are at higher risk of developing AF better than the current scoring systems, the PADS score. This can potentially help doctors provide more targeted and effective treatment to these patients, ultimately aiming to reduce their risk of having another stroke

Mitogen and Stress-Activated Kinases 1 and 2 Mediate Endothelial Dysfunction

Inflammation promotes endothelial dysfunction, but the underlying mechanisms remain poorly defined in vivo. Using translational vascular function testing in myocardial infarction patients, a situation where inflammation is prevalent, and knock-out (KO) mouse models we demonstrate a role for mitogen-activated-protein-kinases (MAPKs) in endothelial dysfunction. Myocardial infarction significantly lowers mitogen and stress kinase 1/2 (MSK1/2) expression in peripheral blood mononuclear cells and diminished endothelial function. To further understand the role of MSK1/2 in vascular function we developed in vivo animal models to assess vascular responses to vasoactive drugs using laser Doppler imaging. Genetic deficiency of MSK1/2 in mice increased plasma levels of pro-inflammatory cytokines and promoted endothelial dysfunction, through attenuated production of nitric oxide (NO), which were further exacerbated by cholesterol feeding. MSK1/2 are activated by toll-like receptors through MyD88. MyD88 KO mice showed preserved endothelial function and reduced plasma cytokine expression, despite significant hypercholesterolemia. MSK1/2 kinases interact with MAPK-activated proteins 2/3 (MAPKAP2/3), which limit cytokine synthesis. Cholesterol-fed MAPKAP2/3 KO mice showed reduced plasma cytokine expression and preservation of endothelial function. MSK1/2 plays a significant role in the development of endothelial dysfunction and may provide a novel target for intervention to reduce vascular inflammation. Activation of MSK1/2 could reduce pro-inflammatory responses and preserve endothelial vasodilator function before development of significant vascular disease

Circulating intermediate monocytes CD14++CD16+ are increased after elective percutaneous coronary intervention

Aim Inflammation plays a central role in the pathogenesis of atherosclerosis and in the sequelae of percutaneous coronary intervention (PCI). Previous work demonstrated that intermediate monocytes (CD14++CD16+) are associated with adverse cardiovascular events, yet monocyte subset response following elective PCI has not been described. This article explores the changes in monocyte subset and humoral response after elective PCI. Methods This prospective study included 30 patients without inflammatory diseases being referred for elective PCI. We included patients treated with drug coated balloons or 2nd generation drug eluting stents. Patients underwent blood tests at baseline (prior to PCI), four hours, two weeks and two months later. Analyses were performed in terms of monocyte subsets (classical CD14++CD16-, intermediate CD14++CD16+ and non-classical CD14+CD16++), gene expression of CD14+ leucocytes and humoral biomarkers. Results Intermediate monocytes decreased significantly four hours after PCI, were recovered at two weeks, and increased significantly at two months post elective, uncomplicated PCI. They remain significantly elevated in the DES group but not in the DCB group. Gene expression analysis of CD14+ leucocytes showed IL18 had decreased expression at two weeks, CXCR4 and IL1β decreased at two months, while pentraxin 3 increased at two weeks and two months. In terms of humoral biomarkers, hsTnI remains elevated up to two weeks post PCI while IL6 and TNFα remain elevated till two months post PCI. Conclusion Intermediate monocytes increase significantly two months following elective, uncomplicated PCI. They remain significantly elevated in the DES group but not in the DCB group suggesting that the PCI strategy could be one of the ways to modulate the inflammatory response post PCI

Atrial fibrillation in embolic stroke of undetermined source: Role of advanced imaging of left atrial function

Background: Atrial fibrillation (AF) is detected in over 30% of patients following an embolic stroke of undetermined source (ESUS) when monitored with an implantable loop recorder (ILR). Identifying AF in ESUS survivors has significant therapeutic implications and AF risk is essential to guide screening with long-term monitoring. The present study aimed to establish the role of Left Atrial (LA) function in subsequent AF identification and develop a risk model for AF in ESUS. Methods: We conducted a single-centre retrospective case-control study including all patients with ESUS referred to our institution for ILR implantation from December 2009 to September 2019. We recorded clinical variables at baseline and analyzed transthoracic echocardiograms in sinus rhythm. Univariate and multivariable analyses were performed to inform variables associated with AF. Lasso regression analysis was used to develop a risk prediction model for AF. The risk model was internally validated using bootstrapping. Results: Three hundred and twenty-three patients with ESUS underwent ILR implantation. In the ESUS population, 293 had a stroke, whereas 30 had suffered a TIA as adjudicated by a senior stroke physician. AF of any duration was detected in 47.1%. Mean follow-up was 710 days. Following lasso regression with backward elimination, we combined increasing lateral PA (the time interval from the beginning of p wave on surface electrocardiogram to the beginning of A’ wave on pulsed wave tissue Doppler of the lateral mitral annulus) (OR 1.011), increasing Age (OR 1.035), higher diastolic blood pressure (DBP) (OR 1.027) and abnormal LA reservoir Strain (OR 0.973) into a new PADS score. The probability of identifying AF can be estimated using the formula: Model discrimination was good (AUC 0.72). The PADS score was internally validated using bootstrapping with 1000 samples of 150 patients showing consistent results with an AUC of 0.73. Conclusions: The novel PADS score can identify the risk of AF on prolonged monitoring with ILR following ESUS and should be considered a dedicated risk-stratification tool for decision-making regarding the screening strategy for AF in stroke

A randomized controlled trial of metformin on left ventricular hypertrophy in patients with coronary artery disease without diabetes:the MET-REMODEL trial

Aim We tested the hypothesis that metformin may regress left ventricular hypertrophy (LVH) in patients who have coronary artery disease (CAD), with insulin resistance (IR) and/or pre-diabetes. Methods and results We randomly assigned 68 patients (mean age 65 ± 8 years) without diabetes who have CAD with IR and/or pre-diabetes to receive either metformin XL (2000 mg daily dose) or placebo for 12 months. Primary endpoint was change in left ventricular mass indexed to height1.7 (LVMI), assessed by magnetic resonance imaging. In the modified intention-to-treat analysis (n = 63), metformin treatment significantly reduced LVMI compared with placebo group (absolute mean difference −1.37 (95% confidence interval: −2.63 to −0.12, P = 0.033). Metformin also significantly reduced other secondary study endpoints such as: LVM (P = 0.032), body weight (P = 0.001), subcutaneous adipose tissue (P = 0.024), office systolic blood pressure (BP, P = 0.022) and concentration of thiobarbituric acid reactive substances, a biomarker for oxidative stress (P = 0.04). The glycated haemoglobin A1C concentration and fasting IR index did not differ between study groups at the end of the study. Conclusion Metformin treatment significantly reduced LVMI, LVM, office systolic BP, body weight, and oxidative stress. Although LVH is a good surrogate marker of cardiovascular (CV) outcome, conclusive evidence for the cardio-protective role of metformin is required from large CV outcomes trials

Circulating intermediate monocytes CD14++CD16+ are increased after elective percutaneous coronary intervention.

Acknowledgements: We would like to thank all staff at the cardiology department at the Norfolk & Norwich University Hospital who facilitated this study.Funder: NIHRFunder: National Institute for Health Research Capability Fund from Norfolk and Norwich University HospitalFunder: Norfolk Heart TrustFunder: B Braun Ltd.AIM: Inflammation plays a central role in the pathogenesis of atherosclerosis and in the sequelae of percutaneous coronary intervention (PCI). Previous work demonstrated that intermediate monocytes (CD14++CD16+) are associated with adverse cardiovascular events, yet monocyte subset response following elective PCI has not been described. This article explores the changes in monocyte subset and humoral response after elective PCI. METHODS: This prospective study included 30 patients without inflammatory diseases being referred for elective PCI. We included patients treated with drug coated balloons or 2nd generation drug eluting stents. Patients underwent blood tests at baseline (prior to PCI), four hours, two weeks and two months later. Analyses were performed in terms of monocyte subsets (classical CD14++CD16-, intermediate CD14++CD16+ and non-classical CD14+CD16++), gene expression of CD14+ leucocytes and humoral biomarkers. RESULTS: Intermediate monocytes decreased significantly four hours after PCI, were recovered at two weeks, and increased significantly at two months post elective, uncomplicated PCI. They remain significantly elevated in the DES group but not in the DCB group. Gene expression analysis of CD14+ leucocytes showed IL18 had decreased expression at two weeks, CXCR4 and IL1β decreased at two months, while pentraxin 3 increased at two weeks and two months. In terms of humoral biomarkers, hsTnI remains elevated up to two weeks post PCI while IL6 and TNFα remain elevated till two months post PCI. CONCLUSION: Intermediate monocytes increase significantly two months following elective, uncomplicated PCI. They remain significantly elevated in the DES group but not in the DCB group suggesting that the PCI strategy could be one of the ways to modulate the inflammatory response post PCI

Assessment of Paclitaxel Drug-Coated Balloon Only Angioplasty in STEMI.

BACKGROUND: Primary percutaneous coronary intervention (pPCI) with drug-eluting stents (DES) has emerged as the standard of care, but stent-related events have persisted. Drug-coated balloon (DCB)-only angioplasty is an emerging technology, although it is not fully evaluated compared with DES in the context of pPCI. OBJECTIVES: The aim of this study was to investigate the safety of DCB-only angioplasty compared with second-generation DES in pPCI. METHODS: All-cause mortality and net adverse cardiac events (cardiovascular mortality, acute coronary syndrome, ischemic stroke or transient ischemic attack, major bleeding, and unplanned target lesion revascularization [TLR]) were compared among all patients treated with DCBs only or with second-generation DES only for first presentation of ST-segment elevation myocardial infarction (STEMI) due to de novo disease between January 1, 2016, and November 15, 2019. Patients treated with both DCBs and DES were excluded. Data were analyzed using Cox regression models, Kaplan-Meier estimator plots and propensity score matching. RESULTS: Among 1,139 patients with STEMI due to de novo disease, 452 were treated with DCBs and 687 with DES. After a median follow-up period of >3 years, all-cause mortality was 49 of 452 and 62 of 687 in the DCB and DES groups, respectively (P = 0.18). On multivariable Cox regression analysis, there was no difference in mortality between DCBs and DES in the full and propensity score-matched cohorts. Age, frailty risk, history of heart failure, and family history of ischemic heart disease remained significant independent predictors of mortality. There was no difference in any of the secondary endpoints, including unplanned TLR. CONCLUSIONS: DCB-only angioplasty appears safe compared with DES for STEMI in terms of all-cause mortality and all net adverse cardiac events, including unplanned TLR. DCB may be an efficacious and safe alternative to DES in selected patient groups. (Drug Coated Balloon Only vs Drug Eluting Stent Angioplasty; NCT04482972)